title: SOCS3 deletion in T lymphocytes suppresses development of chronic ocular inflammation via upregulation of CTLA-4 and expansion of regulatory T cells.
abstract: Suppressors of cytokine signaling (SOCS) proteins are negative-feedback regulators of the JAK/STAT pathway, and SOCS3 contributes to host immunity by regulating the intensity and duration of cytokine signals and inflammatory responses. Mice with Socs3 deletion in myeloid cells exhibit enhanced STAT3 signaling, expansion of Th1 and Th17 cells, and develop severe experimental autoimmune encephalomyelitis. Interestingly, development of the unique IL-17/IFN-γ double-producing (Th17/IFN-γ and Tc17/IFN-γ) subsets that exhibit strong cytotoxic activities and are associated with pathogenesis of several autoimmune diseases has recently been shown to depend on epigenetic suppression of SOCS3 expression, further suggesting involvement of SOCS3 in autoimmunity and tumor immunity. In this study, we generated mice with Socs3 deletion in the CD4 T cell compartment (CD4-SOCS3 knockout [KO]) to determine in vivo effects of the loss of Socs3 in the T cell-mediated autoimmune disease, experimental autoimmune uveitis (EAU). In contrast to the exacerbation of experimental autoimmune encephalomyelitis in myeloid-specific SOCS3-deleted mice, CD4-SOCS3KO mice were protected from acute and chronic uveitis. Protection from EAU correlated with enhanced expression of CTLA-4 and expansion of IL-10-producing regulatory T cells with augmented suppressive activities. We further show that SOCS3 interacts with CTLA-4 and negatively regulates CTLA-4 levels in T cells, providing a mechanistic explanation for the expansion of regulatory T cells in CD4-SOCS3 during EAU. Contrary to in vitro epigenetic studies, Th17/IFN-γ and Tc17/IFN-γ populations were markedly reduced in CD4-SOCS3KO, suggesting that SOCS3 promotes expansion of the Th17/IFN-γ subset associated with development of severe uveitis. Thus, SOCS3 is a potential therapeutic target in uveitis and other autoinflammatory diseases.
authors.affiliation: Molecular Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Cheng-Rong
authors.initials: CR
authors.lastname: Yu
authors.forename: Sung-Hye
authors.initials: SH
authors.lastname: Kim
authors.forename: Rashid M
authors.initials: RM
authors.lastname: Mahdi
authors.forename: Charles E
authors.initials: CE
authors.lastname: Egwuagu
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D060908:CTLA-4 Antigen / Q000096:biosynthesis / Q000378:metabolism*; D002454:Cell Differentiation / Q000276:immunology; D005123:Eye / Q000276:immunology; D007249:Inflammation / Q000235:genetics; D007371:Interferon-gamma / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology; D014605:Uveitis / Q000276:immunology* / Q000517:prevention & control
chemical_list: D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10; D007371:Interferon-gamma